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Chemistry and Pharmacology of Naturally Occurring Flavoalkaloids
Published in Namrita Lall, Medicinal Plants for Cosmetics, Health and Diseases, 2022
Rashmi Gaur, Jyoti Gaur, Nikhilesh Kumar
(-)-licorice glycoside E was the first indole flavoalkaloid identified (51), in 1997, from the roots of Glycyrrhiza uralensis Fisch, commonly known as Tohoku licorice (Figure 21.2) (Hatano et al., 1998). The absolute configuration of 51 was determined with the help of CD spectra. Hubner et al. (1999) isolated the oxindole-flavoalkaloid (52) from the seeds of the horse chestnut Aesculus hippocastanum L. (Figure 21.2). The presence of sugar moieties was confirmed by acid-hydrolysis, semi-synthesis of its derivatives and gas chromatography. Kapusta et al. (2007) isolated from the same plant, and an ion consistent with the deoxy analog 53 was analyzed using mass spectrometry (Figure 21.2) (Kapusta et al., 2007).
Reactivities of Amino Acids and Proteins with Iodine
Published in Erwin Regoeczi, Iodine-Labeled Plasma Proteins, 2019
IC1 and the reactive species generated by chloramine-T are more potent oxidants of tryptophan than I2 or .126 The state of oxidation achieved depends on the stoichiometry of the reactants. Again, this is evident from work on lysozyme; under the conditions132 stated above, the limited amount of iodine is incapable of oxidizing the ring to oxindole. An oxindolyl ester135,136 forms instead between C-2 and the carboxyl group of Glu-35 that is analogous to the state of oxidation of Structure D in Figure 46. This transformation weakens the peptide bond, thus making it sensitive to nonoxidative cleavage.137
Total Synthesis of Some Important Natural Products from Brazilian Flora
Published in Luzia Valentina Modolo, Mary Ann Foglio, Brazilian Medicinal Plants, 2019
Leonardo da Silva Neto, Breno Germano de Freitas Oliveira, Wellington Alves de Barros, Rosemeire Brondi Alves, Adão Aparecido Sabino, Ângelo de Fátima
Another oxindole alkaloid is diaboline 23, which belongs to the same family as strychnine. In 1984, Nicoletti et al. identified this alkaloid from Brazilian biodiversity during their studies with the Strychnos genus. Indeed, Strychnos pseudoquina (Longaniacea; quina-do-campo or falsa-quina), a plant that grows in the Brazilian Cerrado, locally known as “quina do campo” or “falsa quina” and used in regional medicine for the treatment against malaria and other diseases, afforded the (+)-diaboline 23 alkaloid from ethanolic extracts of its ground and dried leaves. The structural complexity of this molecule was evidenced by the synthetic approach undertaken by Ohshima et al. (2004) that accessed this alkaloid in 28 steps and an approximately 1% overall yield (Figure 12.8). The key step comprised a catalytic and enantioselective Michael reaction between malonate 24 and cyclic enone 25, mediated by the AlLibis(binaphthoxide) complex (ALB) (Shimizu et al., 1998; Takayoshi et al., 1996); the improved methodology in this work allowed the Michael adduct 26 to be obtained on a multi-gram scale and in high enantiomeric excess (e.e.). Another very well-delineated strategy was the construction of the BCDE ring system through the domino cyclization process starting from compound 27 in three steps and 66% yield, affording compound 28, which already has the basic core of the desired product. Finally, the (+)-diaboline 23 was achieved in an elegant synthetic route, likely the most efficient from the literature, and can be used in the synthesis of other advanced Strychnos alkaloids. However, some drawbacks can be noted in this approach, such as the formation of a mixture of isomers in some steps, which decreases the overall yield, and an unexpected epimerization of the C-16 stereocenter during the E-ring formation.
Synthesis and biological evaluation of flavonoid-based IP6K2 inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Myunghwan Ahn, Seung Eun Park, Jiyeon Choi, Jiahn Choi, Doyoung Choi, Dongju An, Hayoung Jeon, Soowhan Oh, Kiho Lee, Jaehoon Kim, Jaebong Jang, Seyun Kim, Youngjoo Byun
Since IP6K is considered as a potential target for obesity and metabolic diseases, several synthetic and natural IP6K inhibitors have been described to date.22–25,27,28 One of the synthesised IP6K inhibitors is [N2−(m−(trifluoromethyl)benzyl) −N6−(p−nitrobenzyl)purine] (TNP) (1a), which acts as a competitive inhibitor by interacting with the ATP-binding site of IP6K (Figure 1).22 However, TNP has limitations for clinical use, including its inhibition of cytochrome P450 (CYP450), cellular Ca2+ fluxes, and several off-target kinases, such as CaMK1 and ERK.24,27,29–31 The second compound is an oxindole analog, LI-2242 (1b), which was reported as a potent IP6K inhibitor (IP6K1 IC50: 31 nM, IP6K2 IC50: 42 nM, IP6K3 IC50: 8.7 nM).25 Another oxindole analog, SC-919 (1c), was disclosed by Takeda Pharmaceuticals.32 The latest IP6K inhibitor is a benzisoxazole analog, UNC7467 (1d), which was recently reported as a potent IP6K inhibitor (IP6K1 IC50: 8.9 nM, IP6K2 IC50: 4.9 nM, IP6K3 IC50: 1323 nM) with selectivity of IP6K1 and IP6K2 over IP6K3.23
Development of novel isatin–nicotinohydrazide hybrids with potent activity against susceptible/resistant Mycobacterium tuberculosis and bronchitis causing–bacteria
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Zainab M. Elsayed, Wagdy M. Eldehna, Marwa M. Abdel-Aziz, Mahmoud A. El Hassab, Eslam B. Elkaeed, Tarfah Al-Warhi, Hatem A. Abdel-Aziz, Sahar M. Abou-Seri, Eman R. Mohammed
Concerning the structure–activity relationship, it was observed that the anti-tubercular activity of compounds 5a–5i was affected by two main factors; N-substitution and incorporation of halogen at position 5 of the oxindole ring. Regarding N-substitution it was shown that, compounds bearing isobutyl group: 5b, 5f, and 5h exhibited remarkable activity with MIC values = 1.95, 0.48, and 0.24 µg/mL, respectively. Similarly, compound 5d with N-benzyl moiety revealed a potent activity with MIC = 0.24 µg/mL. In contrast, compounds 5c and 5i carrying the N-ethylcarboxylate group were found to be the least active derivatives (MIC = 7.81 µg/mL). Moreover, the contribution of substitution at position 5 of oxindole ring on the activity was quite important. Incorporating 5-Br group in compounds 5g and 5h (MIC = 0.24 µg/mL) showed better activity than 5-Cl substituted compounds 5e and 5f (MIC = 0.48 and 3.9 µg/mL, respectively) and the unsubstituted congeners 5a–5c (MIC range = 3.9–7.81 µg/mL).
Cytotoxic oxindole derivatives: in vitro EGFR inhibition, pharmacophore modeling, 3D-QSAR and molecular dynamics studies
Published in Journal of Receptors and Signal Transduction, 2019
Sasikala Maadwar, Rajitha Galla
In the current investigation, a series of novel oxindole derivatives were taken which are previously proved for their cytotoxic potentials. Enzyme inhibitory studies suggested that the inhibitory activity of these compounds against EGFR protein could be the reason for the higher cytotoxicity. Molecular docking studies further supported the elucidation of binding patterns of the molecules in EGFR protein environment. Pharmacophore modeling studies identified AAARRR.1003 common pharmacophore model as a valid model, which was also supported by the employed regression analysis. Results from molecular dynamics simulations elucidated the mechanistic insight of EGFR inhibition by oxindole compounds and their binding phenomenon. Further simulations with longer time period may provide deeper insights of ligand interactions in the protein environment. It is noteworthy to use compound 2 as a new scaffold for further development of multifunctional compounds.